Background: Severe sepsis, defined as a systemic inflammatory response to infection associated with acute organ dysfunction, is common among surgical patients and is a major cause of morbidity and mortality. Severe sepsis has been associated with changes in inflammatory and hemostatic biomarkers. In patients undergoing surgical procedures there may be additional stimulation of cytokine release and activation of the coagulation system. The purpose of this study was to characterize the baseline differences in biomarkers between surgical and non-surgical patients. In addition, we assessed the dynamic changes in biomarkers and coagulation parameters in surgical patients with severe sepsis enrolled in PROWESS and treated with placebo or drotrecogin alfa (activated). Methods: A blinded PROWESS surgical evaluation committee (SEC) verified patients as having undergone a relevant operative procedure within 30 days of enrollment for inclusion in the surgical cohort of PROWESS. At baseline and on study days 1-7, biomarkers and coagulation parameters available for analysis were D-dimer, interleukin-6 (IL-6), protein C activity, protein S activity, anti-thrombin III (ATIII), activated partial thromboplastin time (aPTT), and prothrombin time (PT). Platelet count was determined at baseline only. Baseline values were compared between SEC-defined surgical and all other non-surgical patients, and between pre- and post-operative surgical patients from the PROWESS trial. Changes from baseline were compared between drotrecogin alfa (activated)-treated and placebo-treated surgical patients. Statistical analyses were performed using ANOVA on the ranked values. Results: The SEC verified 474 (28%) of the 1,690 PROWESS patients as surgical. Median D-dimer, IL-6, aPTT and PT values were significantly higher at baseline for surgical patients than non-surgical patients (p < 0.001). Surgical patients had significantly lower median protein C, protein S, and ATIII activity at baseline than non-surgical patients (p < 0.001). Surgical patients treated with drotrecogin alfa (activated) showed a significant decrease in D-dimer levels on study days 1-5 (p < 0.05), and a more rapid increase in Protein C levels on study days 1-4 (p < 0.05) compared to placebo. Conclusions: Surgical patients with severe sepsis appear to have a higher severity of illness at baseline as demonstrated by derangements in biomarkers and coagulation markers compared to non-surgical patients. Surgical patients treated with drotrecogin alfa (activated) showed reduced D-dimer concentrations and a more rapid increase in protein C concentrations during the infusion period.